Infection remains the most frequent illness of man and bacterial infections one of the most common causes of death. The investigations proposed here seek to gain understanding of the physiology of host defense against infection, especially bacterial, and of the biochemical basis for the predisposition to bacterial infection in certain disease states. More effective prevention and management of infections in the normal or compromised host and the eventual manipulation of the immune system to enhance its protective effects are the ultimate goals. Mechanisms involved in the interaction of bacteria and polymorphonuclear and mononuclear phagocytes, antibody, and complement activated through the classical or alternative pathways will be studied in the following specific projects: (1) Studies of the mechanism of bacterial and fungal killing by phagocytes and of the role of phagocytes in inflammatory tissue damage. The mechanism by which neutrophils convert oxygen to superoxide anion, hydrogen peroxide, and hydroxyl radical will be studied. The relationship of this mechanism to plasma membrane Fc and C3b receptors, its modulation by intracellular Ca ions and cyclic nucleotides, its location (membrane or granular), and its suppression by pharmacologic agents will be explored. (2) Studies of the generation of microbicidal oxygen metabolites by cultured human and mouse macrophages. The oxidative metabolic concomitants of macrophage activation will be sought, and oxygen-dependent and independent killing of Candida will be compared in normal and activated cells. (3) Studies of the role of the alternative complement pathway in resistance to bacterial infection. The effects on this mechanism of sickle cell disease, splenectomy and malnutrition will be studied and correlated with predisposition to bacterial infection.